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WO2012034032A2 - Solutions antimicrobiennes - Google Patents

Solutions antimicrobiennes Download PDF

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Publication number
WO2012034032A2
WO2012034032A2 PCT/US2011/051020 US2011051020W WO2012034032A2 WO 2012034032 A2 WO2012034032 A2 WO 2012034032A2 US 2011051020 W US2011051020 W US 2011051020W WO 2012034032 A2 WO2012034032 A2 WO 2012034032A2
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WO
WIPO (PCT)
Prior art keywords
edta
composition
catheter
chelator
alcohol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2011/051020
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English (en)
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WO2012034032A8 (fr
WO2012034032A3 (fr
Inventor
Issam Raad
George Abiaad
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BOARD OF REGENTS OF UNBIVERSITY OF TEXAS SYSTEM
University of Texas System
Original Assignee
BOARD OF REGENTS OF UNBIVERSITY OF TEXAS SYSTEM
University of Texas System
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Priority to US13/821,546 priority Critical patent/US9565857B2/en
Publication of WO2012034032A2 publication Critical patent/WO2012034032A2/fr
Publication of WO2012034032A8 publication Critical patent/WO2012034032A8/fr
Publication of WO2012034032A3 publication Critical patent/WO2012034032A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/02—Acyclic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
    • A01N31/14—Ethers
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
    • A61L2/186—Peroxide solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A61L2103/15—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/206—Biguanides, e.g. chlorohexidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to the fields of medicine and microbiology. More particularly, it concerns methods of reducing microbial organisms from surfaces, including indwelling medical devices, medical equipment and other surfaces, for example.
  • Household and institutional chlorine bleaches contain 5.25% active sodium hypochlorite when they are manufactured. The remaining 94.75% is primarily water. Chlorinated compounds such as sodium hypochlorite when diluted in water form hypochlorous acid. This acid is extremely effective against many types of microorganisms including bacteria, fungi and viruses. For instance, the product label for Purex household bleach claims it is effective against Staphylococcus and Streptococcus bacteria, Influenza A and B viruses and athletes foot fungus. However, the label also says a surface must be pre-cleaned before using the chlorine bleach solution.
  • Chlorine bleach can emit a carcinogenic gas if it comes in contact with formaldehyde, or is hyper-chlorinated by hot water; 6. extremely corrosive to metals - Chlorine bleach can attack and corrode metal surfaces as well as permanently discolor countertops; 7. discolor fibers and colored surfaces - carpets, entrance matting and clothing are just a few of the fibers that can be damaged when contacted by chlorine bleach solutions; 8. damage floor finishes - Chlorine bleach can attack the floor finish coatings on the floor requiring them to be removed and replaced; 9. rapidly inactivated by organic debris (blood, tissue, saliva, microbes); 10. diluted solutions quickly lose their effectiveness. Chlorine bleach is unstable and can lose its oxidizing and disinfecting strength rapidly compared to "quat" based disinfectant-cleaners and/or sanitizers.
  • Phenols or phenolic disinfectant-cleaners are not as corrosive as chlorine bleach. But they are aggressive enough to attack and damage floor finishes and sensitive flooring. Phenolic disinfectants are still the preferred product in a few health care facilities. They are used in areas where gross contamination of blood and body fluids subsist. Phenolics are effective against pathogenic bacteria like tubercle bacillus that cause tuberculosis.
  • phenolic disinfectants and many institutions do not commonly use phenolic products because of the following: 1. can be toxic to skin and eyes (depigmentation can occur with long periods of exposure or use); 2. commonly causes sinus and respiratory tract irritation or problems; 3. corrosive to certain rubber and plastic surfaces; 4. Flammable; 5. can leave a film on a cleaned surface, creating a buildup that will eventually need removal; 6. solutions need to be discarded and remixed daily; and 7. Expensive.
  • Quarternary ammonium chlorides or "quats" as they are commonly known are based upon the active ingredient benzalkonium chloride. These quaternary salt compounds can be formulated with a variety of ingredients to provide a safe and effective neutral pH, disinfectant-cleaner without damaging floor finishes or sensitive floor surfaces. Quats are effective in destroying a broad spectrum of harmful microorganisms. They are effective in killing many pathogenic microorganisms while cleaning the surfaces upon which they reside - all in one simple step. There are disadvantages of quaternary ammonium chlorides as follows: 1. quaternary ammonium chlorides do not kill tuberculosis; 2. do not perform especially well when challenged by organic soil.
  • Quaternary ammonium chlorides do not provide residual activity on hard surfaces.
  • the biggest single problem with the use of quaternary ammonium chlorides is their inconsistent efficacy against moulds, particularly Aspergillus; 3. quaternary ammonium chlorides have also had trouble with ever-present microorganisms such as E. coli and Pseudomonas; 4. quaternary ammonium chlorides have been suspected in developing microorganism's resistance to QAC quaternary ammonium chlorides after long periods of reappeared use.
  • Alcohols such as Ethyl and Isopropyl Alcohol, for example
  • Ethanol and Isopropyl alcohol are both excellent disinfectants whose germicidal properties are generally underestimated. Both are rapidly bactericidal against vegetative bacterial forms, tuberculocidal, fungicidal, and virucidal.
  • the disinfectant properties of both ethanol and isopropyl alcohol rapidly drop at concentrations below fifty percent (50%) and above ninety percent (90%). The recommended concentration for use is sixty - ninety percent (60 - 90%) by volume.
  • the present invention overcomes these and other limitations in the art and provides compositions that reduce or eradicate microbial agents from surfaces, for example.
  • the present invention regards combinations of compounds for antimicrobial activity.
  • the present invention concerns methods and compositions related to one or more guanidium compounds and one or more glycol ethers, optionally with an additional agent.
  • Exemplary additional agents include one or more alkyl polyglycosides, one or more alcohols, deoxycholate, one or more chelators, and/or glycerol.
  • the compositions are suitable for antimicrobial activity on any surface, including any organic or inorganic surface.
  • the antimicrobial composition of the invention is employed for the following: 1) environmental disinfectant; 2) skin and/or mucosal sanitizer; 3) pipeline; and 4) lock solution for catheters.
  • an environmental disinfectant or an oral or skin sanitizer with active disinfectant activity there is an environmental disinfectant or an oral or skin sanitizer with active disinfectant activity.
  • the present invention regards a germicidal disinfectant for wide use that inactivates virtually all recognized pathogenic microorganisms.
  • the disinfectant has rapid decontaminating activity resulting in the killing of organisms and the removal of the contamination after use with no quantitative implication.
  • the present invention concerns novel, environmentally safe, and highly effective disinfectant chlorhexidine in combination with bioenhancing surfactants and detergents.
  • the detergents include an alkyl polyglycoside, such as Glucopon®, a glycol ether, such as 2-(2-ethoxyethoxy)ethanol (Dowanol®; The Dow Chemical Company, Midland, Michigan) and/or deoxycholate, for example.
  • guanidium compounds such as chlorhexidine
  • one or more bioenhancers such as Dowanol
  • surfactants such as Glucopon® and/or detergent such as deoxycholate further enhances the activity of the combination of chlorhexidine and Dowanol, for example.
  • Dowanol® is an unexpected bioenhancer of chlorhexidine in a manner superior to Glucopon® plus chlorhexidine.
  • Glucopon® enhances the activity of the combination CHX plus low concentration of Dowanol® (3%) in a manner superior to CHX plus Glucopon® alone.
  • chlorhexidine is utilized in combination with Dowanol® with or without Glucopon® or Deoxycholate as a disinfectant and has a variety of applications, such as for a skin sanitizer, mouthwash, catheter lock solution, etc.
  • Particular aspects of the invention include chlorhexidine in combination with 50% glycerol as a disinfectant, including for a skin sanitizer, a catheter lock solution, or mouthwash because of the unique activity of this combination as well as the CHX plus Dowanol® against bacteria and biofilm that embed the lumen of the catheter and/or cavity.
  • One, two, or more of biguanide compounds may be used in the invention, such as chlorhexidine salts, including chlorhexidine (also known as 1,1'- hexamethylene-bis-[5-(4-chlorophenyl) -biguanide]), widely used in the form of its salts (such as the acetate, hydrochloride, and gluconate salts, for example).
  • chlorhexidine salts including chlorhexidine (also known as 1,1'- hexamethylene-bis-[5-(4-chlorophenyl) -biguanide]
  • salts such as the acetate, hydrochloride, and gluconate salts, for example.
  • Other known biguanide-based disinfectants are, for example, the salts of polyhexamethylene biguanide compounds as described in U.S. Patent No. 4,748,158, which is incorporated by reference herein in its entirety.
  • exemplary antimicrobial biguanide compounds that can be utilized in the present invention include N 1 -(4-chlorobenzyl)-N 5 -(2,4- dichlorobenzyl)-biguanide; p-chlorophenyl biguanide; 4-chlorobenzhydryl biguanide; N-3-lauroxypropyl-N 5 -p-chlorobenzyl biguanide; N 1 -p-chlorophenyl-N 5 -lauryl biguanide and the non-toxic addition salts thereof, especially gluconates and acetates.
  • Dowanol® is employed in the invention.
  • This refers to Dipropylene Glycol n- Butyl Ether (C 4 H 9 0[CH 2 CH(CH 3 )0] 2 H. It is a relatively slow-evaporating solvent having properties such as excellent surface tension lowering activity. It has a number of properties that contributed to high latex film quality: it has high polymer plasticizing efficiency; large molecular size and greater polymer mobility contribution; strong partitioning to the polymer phase; relatively slow evaporation rate. It is useful as a cleaning product by itself or when blended with other products.
  • Glucopon® reagents are nonionic surfactants employed in the combination. They combine the formulation ease of typical nonionics with the foam characteristics of anionics.
  • Glucopon® reagents are aqueous solutions of alkyl polyglycosides based on natural fatty alcohol (C10-C16). It is a good detergent and in addition to wetting, dispersing, and interfacial tension reduction properties for increased soil removal and emulsification, it also is soluble in concentrated electrolytes and will other hydrotope less soluble ingredients. It is useful in applications where micellar solubilization, emulsification, and detergency are needed. It is soluble and stable in liquid formulations having high levels of builders and electrolytes. It is compatible and can by synergistic with enzymes, optical brightness, and other surfactants, including cationics, in certain embodiments.
  • deoxycholate is employed.
  • Sodium deoxycholate is a water-soluble ionic detergent used for cell lysis, membrane protein and lipid isolation, liposome preparation, and other applications.
  • the detergent is used to supplement cell culture media and to prevent nonspecific binding in affinity chromatography. It is an effective reagent for removing lipopolysaccharides from immobilized poly mixin B, allowing reuse of this ligand for additional endotoxin removal.
  • antimicrobial solutions may be used to rapidly reduce or eradicate microbial agents from surfaces.
  • MRSA as a form of Gram-positive bacteria
  • E. coli as a form of resistant Gram-negative bacteria
  • C. glabrata as a form of resistant fungi
  • the present invention may be provided on the surface of medical supplies, including medical supplies, tools, devices, gauze, sponges, and so forth.
  • the disinfectant may be provided on the surface of a medical device, a pipe, a floor, a table-top, a counter-top, an eating surface, a toy, a high chair, medical equipment, a wheel chair, a phone, a computer, a kitchen sponge, a faucet, light switch cover, a door knob, a door, razor, manicure or pedicure equipment, personal digital assistant, an MP3 player, upholstery, a water fountain, wall, razor, manicure and/or pedicure equipment, personal digital assistant, MP3 player, upholstery, bed linens, toilet, vanity, paper towel dispenser, telephone, store cart, or water fountain, and so forth.
  • the surface may be coated and/or impregnated, for example.
  • the disinfectant may be employed as an oral or skin sanitizer, it may be provided as a stand-alone skin decontamination composition, such as a hand gel, or it may be provided with other reagents, such as with a soap, including a hand soap, or with a mouthwash, toothpaste, or floss coating.
  • the disinfectant may be employed as an cleanser itself or may be a component of a cleanser having multiple disinfectants.
  • antimicrobial solutions comprising at least one glycol ether and at least one guanidinium compound, and/or at least one chelator, and/or at least one alkylpolyglucoside, and/or glycerol, and/or deoxycholate.
  • one or more non-ionic surfactants may be included in an antimicrobial composition of the present invention.
  • an antimicrobial composition comprising the glycol ether, dipropylene glycol n-butyl ether, the guanidium compound chlorhexidine; an alkylpolyglucoside such as, for example, capryl glucoside, decyl glucoside, coco- glucoside, or lauryl glucoside; an alcohol (e.g., ethanol or isopropyl alcohol); and/or a chelator (e.g., CaEDTA).
  • Alkylpolyglucosides are commercially available as GlucoponTM products from Cognis (Monheim, Germany), for example.
  • alkylpolyglucoside refers to a compound having the following structure:
  • R is an C 2 -C 20 alkyl, more preferably a C 4 -C 14 alkyl.
  • R may be a C n alkyl, wherein n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • R is an unsubstituted alkyl; it is nonetheless anticipated that R may be a substituted alkyl in various embodiments.
  • the alkyl glycoside potentiating agents utilized in accordance with the present invention may be derived using known procedures from fatty alcohols and sugars. Procedures for preparing the alkyl glycoside component of the present invention are well known, as for example illustrated in U.S. Pat. No. 3,598,865. For example, the Fisher process of producing alkyl mono glycosides involves heating glucose and a lower alcohol with an acid catalyst.
  • antimicrobial agents including one or more antibacterial agents, and/or one or more antifungal agents, and/or one or more antiviral agents, and/or one or more antiseptic agents, and/or combinations thereof.
  • the antimicrobial agent is an antibacterial agent. While any antibacterial agent as described herein may be used in the instant antimicrobial solutions, some non-limiting additional exemplary antibacterial agent(s) that may be used in the antimicrobial composition include those classified as aminoglycosides, beta lactams, quinolones or fluoroquinolones, macrolides, sulfonamides, sulfamethaxozoles, tetracyclines, streptogramins, oxazolidinones (such as linezolid), clindamycins, lincomycins, rifamycins, glycopeptides, polymxins, lipo-peptide antibiotics, as well as pharmacologically acceptable sodium salts, pharmacologically acceptable calcium salts, pharmacologically acceptable potassium salts, lipid formulations, derivatives and/or analogs of the above.
  • the antimicrobial agent of the present invention further includes an antifungal agent.
  • antifungal agents include imidazoles or triazoles such as clotrimazole, miconazole, ketoconazole, econazole, butoconazole, omoconazole, oxiconazole, terconazole, itraconazole, fluconazole, voriconazole (UK 109,496), posaconazole, ravuconazole or flutrimazole; the polyene antifungals such as amphotericin B, liposomal amphoterecin B, natamycin, nystatin and nystatin lipid formualtions; the cell wall active cyclic lipopeptide antifungals, including the echinocandins such as caspofungin, micafungin, anidulfungin, cilofungin; LY121019; LY303366; the allylamine group
  • antifungal agents include naftifine, tolnaftate, mediocidin, candicidin, trichomycin, hamycin, aurefungin, ascosin, ayfattin, azacolutin, trichomycin, levorin, heptamycin, candimycin, griseofulvin, BF-796, MTCH 24, BTG-137586, pradimicins (MNS 18184), benanomicin; ambisome; nikkomycin Z; flucytosine, or perimycin.
  • the antimicrobial agent of the present invention further includes an antiviral agent.
  • antiviral agents include cidofovir, amantadine, rimantadine, acyclovir, gancyclovir, pencyclovir, famciclovir, foscarnet, ribavirin, or valcyclovir.
  • the antimicrobial agent is an innate immune peptide or proteins.
  • the antimicrobial agent of the present invention further comprises an antiseptic agent.
  • antiseptic agents include a taurinamide derivative, a phenol, a quaternary ammonium surfactant, a chlorine-containing agent, a quinaldinium, a lactone, a dye, a thiosemicarbazone, a quinone, a carbamate, urea, salicylamide, carbanilide, a guanide, an amidine, an imidazoline biocide, acetic acid, benzoic acid, sorbic acid, propionic acid, boric acid, dehydroacetic acid, sulfurous acid, vanillic acid, esters of p- hydroxybenzoic acid, isopropanol, propylene glycol, benzyl alcohol, chlorobutanol, phenylethyl alcohol, 2-bromo-2-nitropropan-1,3-diol, formaldehyde, glutaraldehyde, calcium hypochlorite, potassium hypochlorite, sodium
  • the antiseptic agent is as set forth in the specification of U.S. Provisional Application Serial No. 60/261,447, U.S. Provisional Application Serial No. 60/316,165, and U.S. Non-Provisional Patent Application Serial No. 10/044,842, incorporated herein by reference in their entirety.
  • the antiseptic agent comprises a basic reagent and a dye.
  • the basic reagent may be a guanidium compound, a biguanide, a bipyridine, a phenoxide antiseptic, an alkyl oxide, an aryl oxide, a thiol, a halide, an aliphatic amine, or an aromatic amine.
  • the basic reagent is a guanidium compound.
  • Non-limiting examples of guanidium compounds include chlorhexidine, alexidine, hexamidine.
  • the basic reagent is a bipyridine.
  • One example of a bipyridine is octenidine.
  • the basic reagent is a phenoxide antiseptic.
  • the dye may be a triarylmethane dye, a monoazo dye, a diazo dye, an indigoid dye, a xanthene dye, an anthraquinone dye, a quinoline dye, an FD&C dye.
  • triarylmethane dye include gentian violet, crystal violet, ethyl violet, or brilliant green.
  • Exemplary monoazo dyes inlude FD&C Yellow No. 5, or FD&C Yellow No. 6.
  • Other non-limiting examples of FD&C dye include Blue No. 1 or Green No. 3.
  • One non-limiting example of diazo dyes is D&C Red No. 17.
  • An example of an indigoid dye is FD&C Blue No. 2.
  • An examples of a xanthene dye is FD&C Red No. 3; of an anthraquinone dye is D&C Green No. 6; and of an quinoline dye is D&C Yellow No. 1.
  • antiseptic agents that may be used to prepare the antimicrobial solutions of the invention are gendine, genlenol, genlosan, or genfoctol.
  • chelator agents are contemplated as useful in the antimicrobial solutions of the invention. This includes chelators such as EDTA free acid, EDTA 2Na, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH 4 , EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTACu(II)-EDTA, Dy(III)-EDTA, Eu(III)-EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, CyDTA, DHEG, diethylenetriamine penta acetic acid (DTPA), DTPA-OH, EDDA, EDDP, EDDPO, EDTA-OH, EDTPO, EGTA, HBED, HDTA, HIDA, IDA, Methyl-EDTA, NTA, NTP, NTPO, O-Bistren,
  • EDTA free acid
  • at least one anticoagulant such as heparin, hirudin, EGTA, EDTA, urokinase, streptokinase, hydrogen peroxide etc.
  • a variety of alcohols are contemplated as useful in the preparation of the instant antimicrobial solution, and include any antimicrobially active alcohol. Non-limiting examples of alcohols include ethanol, methanol, isopropanol, propylene glycol, benzyl alcohol, chlorobutanol, phenylethyl alcohol, and the like.
  • the concentration of the alcohol is preferably in the range of 5%-80% (v/v), more preferably in the range of 10% to 50%, more preferably in the range of 15% to 40%, more preferably in the range of 20% to 30%, with the most preferable being about 25%.
  • the more preferred concentration of alcohol will include 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% (v/v) of the alcohol in the preparation of the instant antimicrobial solutions. This includes the use of intermediate concentrations of alcohol such as 11%, 22.5%, 26% and the like.
  • solutions of the instant invention can comprise various combinations of at least one alcohol, at least one antimicrobial agent, and at least one chelator/anticoagulant.
  • the solution of the invention comprises at least one alcohol and at least one chelator/anticoagulant.
  • such an antimicrobial solution comprises ethanol and EDTA or heparin.
  • the invention also provides methods for reducing microbial organisms from a surface comprising: a) obtaining an antimicrobial solution of the invention as set forth herein; and b) contacting the surface with the antimicrobial solution, whereby said contacting reduces microbial organisms from the surface.
  • the contacting is performed for 4 hours or less. In other embodiments of the method, the contacting is performed for 2 hours or less, for 1 hour or less, for 30 minutes or less, or for 15 minutes or less, for 10 minutes or less, for 9 minutes or less, for 8 minutes or less, for 7 minutes or less, for 6 minutes or less, for 5 minutes or less, for 4 minutes or less, for 3 minutes or less, for 2 minutes or less, for 1 minutes or less, for 45 seconds or less, for 30 seconds or less, or for 20 seconds or less. [0041] In another aspect, the method further comprises eradicating microbes from the surface wherein the contacting is performed for about 15 minutes or more.
  • the methods of the invention can be used to reduce microbial agents from the surface of a medical device such as a catheter, a sponge, a gauze, a bandage, an endotracheal tube, a nephrostomy tube, a biliary stent, an orthopedic device, a prosthetic valve, a medical implant, dental devices or dental implants, cardiac assist devices, vascular grafts, tracheostomy, ventriclulostomy devices, or intrathecal devices.
  • a medical device such as a catheter, a sponge, a gauze, a bandage, an endotracheal tube, a nephrostomy tube, a biliary stent, an orthopedic device, a prosthetic valve, a medical implant, dental devices or dental implants, cardiac assist devices, vascular grafts, tracheostomy, ventriclulostomy devices, or intrathecal devices.
  • the catheter is an indwelling catheter such as a central venous catheter, a peripheral intravenous catheter, an arterial catheter, a Swan- Ganz catheter, a hemodialysis catheter, an urinary catheter, a peritoneal catheter, an umbilical catheter, a percutaneous nontunneled silicone catheter, a cuffed tunneled central venous catheter or a subcutaneous central venous port.
  • a central venous catheter such as a central venous catheter, a peripheral intravenous catheter, an arterial catheter, a Swan- Ganz catheter, a hemodialysis catheter, an urinary catheter, a peritoneal catheter, an umbilical catheter, a percutaneous nontunneled silicone catheter, a cuffed tunneled central venous catheter or a subcutaneous central venous port.
  • the methods of the invention are useful in reducing microbial agents from a surface such as an organic surface or an inorganic surface.
  • An organic surface is exemplified by skin, surgical sutures, mucosal membrane surface, or an epithelial surface.
  • the antimicrobial composition may be swabbed on a human body at a site to be the point of incision.
  • An inorganic surface may be the surface of a pipe or pipeline, a floor, a table-top, a counter-top, hospital equipment, or a wheel chair, etc.
  • a pipe is an oil pipeline, a water pipeline, an ice machine pipe, or a beverage dispensing pipe.
  • the antimicrobial solutions of the present invention will find particular usefulness as antimicrobial mouthwash solutions and/or in toothpaste and/or on floss.
  • Such mouthwash solutions are contemplated to be useful both in conjunction with dental procedures and oral sterilization as well as in general dental and oral hygiene applications.
  • Antimicrobial mouthwash is becoming extremely important in the prevention of oral cavity infections as well as aspiration pneumonia. Microbial organisms in the mouth particularly around the teeth, embed themselves in biofilm and the pathogenesis of infection and colonization is similar to that seen in, for example, vascular catheters.
  • the triple combinations of the present invention that will include an antimicrobial (possibly antiseptic) with EDTA and low concentration alcohol as a mouthwash or mouth flush solution.
  • the antimicrobial composition of the present invention is employed to reduce caries.
  • the disinfecting compositions include one or more suitable flavorings, for example, methyl salicylate, peppermint oil, sassafras oil and aniseed oil.
  • suitable flavorings for example, methyl salicylate, peppermint oil, sassafras oil and aniseed oil.
  • the flavorings are generally used in quantities of from about 0.01 to 2.0% by weight, for example.
  • sweeteners may be used in quantities of from about 0.05 to about 2% by weight, for example.
  • the invention also provides a kit for disinfecting a surface to reduce microorganisms thereon, wherein the kit comprises components including at least one antimicrobial composition of the present invention contained in a suitable container.
  • the components of the antimicrobial composition may be combined in a single container, or powdered components may be lyophilized, combined and separately compartmentalized, or all of the components may be placed in separate containers. In some embodiments, only one, two, or three of the components of the antimicrobial composition is included as a dried powder.
  • the kit may optionally include a second carrier solution for reconstituting the lyophilized antibiotic agent(s).
  • Kits in accordance with the present invention may be used to reduce/eliminate microbes on the surface of a medical device, a pipe, a floor, a table- top, a counter-top, an eating surface, a toy, a high chair, medical equipment, a wheel chair, a phone, a computer, a kitchen sponge, a faucet, light switch cover, a door knob, a door, razor, manicure or pedicure equipment, personal digital assistant, an MP3 player, upholstery, a water fountain, wall, razor, manicure or pedicure equipment, personal digital assistant, MP3 player, upholstery, bed linens, or water fountain. It is also contemplated that the kits of the invention will further comprise a means for introducing the kit components into the medical device, the pipe or surface.
  • a syringe or vial comprising a lyophilized unit dose of a pharmacologically effective amount of one or more of the three components of the flush solutions of the present invention.
  • a syringe or vial may further comprises a preselected amount of an ethanol solution such that when the ethanol solution is mixed with the lyophilized unit dose, the desired concentration of the particular agent is obtained.
  • a locking solution for filling and/or flushing a medical indwelling device such as, but not limited to, an implanted catheter is contemplated.
  • the locking solution may comprise at least one antimicrobial composition of the present invention.
  • the antimicrobial agent is effective against Gram-positive and/or Gram-negative bacteria.
  • the disinfectant is useful against pathogenic bacteria.
  • the antimicrobial agent is effective against one or more bacteria selected from the group consisting of the following phyla: 1) Aquificae; 2) Xenobacteria; 3) Fibrobacter; 4) Bacteroids; 5) Firmicutes; 6) Planctomycetes; 7) Chrysogenetic; 8) Cyanobacteria; 9) Thermomicrobia; 10) Chlorobia; 11) Proteobacteria; 12) Spirochaetes; 13) Flavobacteria; 14) Fusobacteria; and 15) Verrucomicrobia.
  • the disinfectants of the present invention are useful against Gram positive cocci; Gram negative cocci; Gram positive bacilli; Gram negative bacilli, Spirochaetes, Rickettsia, and Mycoplasma.
  • the present invention is useful against one or more bacteria that are resistant to one or more antibacterial agents, such as one or more antibiotics.
  • the disinfectants are useful against
  • the disinfectants are useful against Staphylococcus aureus, Listeria monocytogenes, Clostridium botulinum, Legionella pneumophila, E.
  • alcaligenes other Pseudomonas sp, Stenotrophomonas maltophilia, Brucella, Bordetella, Francisella, Legionella spp, Leptospira sp, Bacteroides fragilis, other Bacteroides sp, Fusobacterium sp, Prevotella sp, Veillonella sp, Peptococcus niger, Peptostreptococcus sp, Actinomyces, Bifidobacterium, Eubacterium, and Propionibacterium spp, Clostridium botulinum, C. perfringens, C.
  • Aeromonas hydrophila Chromobacterium violaceum, Pasturella multocida, Plesiomonas shigelloides, Actinobacillus actinomycetemcomitans, Bartonella bacilliformis, B. henselae, B. quintana, Eikenella corrodens, Haemophilus influenzae, other Haemophilus sp, Mycoplasma pneumonia, Borrelia burgdorferi, Treponema pallidum Campylobacter jejuni, Helicobacter pylori, Vibrio cholerae, V. vulnificus, Chlamydia trachomatis, Chlamydophila pneumoniae, C.
  • the antimicrobial agent is effective against one or more viruses, including one or more pathogenic viruses.
  • the antimicrobial agent is effective against one or more viruses selected from the group consisting of Adenoviridae, Picornaviridae, Herpesviridae, Hepadnaviridae, Flaviviridae, Retroviridae, Orthomyxoviridae, Parvoviridae, Paramyxoviridae, Papovaviridae, Polyomavirus, Rhabdoviridae, and Togaviridae.
  • viruses include, for example, HIV, Adenovirus Influenza A, Rabies virus, Hepadnavirus, Varicella-zoster virus, Herpes simplex virus (types 1 and 2), Ebolavirus, Epstein Barr virus, Varicella-zoster virus, pox virus (including smallpox, copox, or monkey pox), human cytomegalovirus, poliovirus, coxsackievirus, Rubeola virus (paramyxovirus), Rubella virus, Variola virus, Avian flu virus (Influenza A virus), hepatitis A, B, and C viruses, parainfluenza, mumps virus, measles virus, respiratory syncitial virus, West Nile virus, Dengue fever virus, yellow fever virus, foot and mouth disease virus, and severe acute respiratory syndrome (SARS) coronavirus.
  • HIV HIV
  • Adenovirus Influenza A Rabies virus, Hepadnavirus
  • Varicella-zoster virus Herpes simplex virus (types 1 and 2),
  • the antimicrobial agent is effective against one or more fungi, including one or more pathogenic fungi.
  • the antimicrobial agent is effective against one or more fungi selected from the group consisting of Histoplasma, Aspergillus and other common household molds, Candida, Cryptococcus, Stachybotrys, Zygomycosis, Fusarium, Blastomycosis, Coccidioides, Scedosporium, and Pneumocystis.
  • the antimicrobial composition is employed against prions.
  • the present invention may be employed as a disinfectant for the benefit of a mammal, including a human, dog, cat, cow, horse, pig, sheep, goat, and so forth.
  • the antimicrobial composition is applied to the teets of a cow prior to milking or to chicken eggs.
  • an antimicrobial composition comprising at least one biguanide and at least one glycol ether.
  • the method further comprises at least one of the following agents: a) an alkylpolyglucoside, wherein the alkylpolyglucoside has the structure:
  • R is an C2-C20 alkyl (such as C4-C14 alkyl), b) deoxycholate, c) at least one chelator, d) at least one alcohol, and/or e) glycerol.
  • the anticmicrobial composition comprises a biguanide, a glycol ether, and an alkylpolyglucoside.
  • the composition comprises a biguanide, a alkylpolyglucoside, a chelator, and an alcohol.
  • the composition comprises a biguanide, glycol ether and deoxycholate.
  • the composition comprises a biguanide, a glycol ether, an alkylpolyglucoside, and deoxycholate.
  • the alkylpolyglucoside is selected from the group consisting of capryl glucoside, decyl glucoside, coco-glucoside, and lauryl glucoside.
  • the guanidium compound is selected from the group consisting of chlorhexidine, alexidine, hexamidine.
  • the glycol ether is dipropylene glycol n-butyl ether.
  • the chelator is selected from the group of chelators consisting of EDTA free acid, EDTA 2Na, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH4, EDTA 3K, Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTACu(II)-EDTA, Dy(III)-EDTA, Eu(III)- EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, CyDTA, DHEG, diethylenetriamine penta acetic acid (DTPA), DTPA-OH, EDDA, EDDP, EDDPO, EDTA-OH, EDTPO, EGTA, HBED, HDTA, HIDA, IDA, Methyl-EDTA, NTA, NTP, NTPO, O-Bistren, TTHA, EGTA, DMSA, defero
  • the concentration of guanidinium compound is about 0.01%-6%; the concentration of dipropylene glycol n-butyl ether is about 1%-12%; the concentration of alkylpolyglucoside is about 0.1%-10%; the concentration of chelator is about 0.1%-20%; and/or the concentration of alcohol is in the range of about l%-80%. In some cases, the concentration of alcohol is in the range of about 15-30%. In particular aspects, the concentration of alcohol is less than about 10% and may be from about 0.25% to about 5%, in certain embodiments. In particular embodiments, the alcohol is ethanol, and wherein the chelator is EDTA or CaEDTA.
  • a method for reducing microbial organisms from a surface or preventing growth of microbial organisms comprising contacting the surface with an antimicrobial composition of the invention.
  • the contact of surfaces may be further defined as impregnating at least part of the surface with the antimicrobial composition.
  • Contact can be for any duration, although in specific embodiments the contacting is performed for 1 hour or less, such as for 15 minutes or less, including for about from 10 seconds, 15, second, 20 seconds, 25 seconds, 30 seconds, 45 seconds, 1 minute, 1.5 minutes, 2 minutes 2.5 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, to about 5 minutes.
  • Surfaces contacted by the antimicrobial composition may be of any kind that harbor one or more pathogenic entities.
  • the surface may be the surface of medical equipment, such as a bed, computer, glove, clothing, ice machine, forceps, scalpel, syringe, or clamp.
  • the surface may be a medical device, such as a patch, sponge, gauze, bandage, a catheter, an endotracheal tube, a nephrostomy tube, a chest tube, a stent, an orthopedic device, a prosthetic valve, a medical implant, dental devices or dental implants, cardiac assist devices, vascular grafts, tracheostomy, ventriclulostomy devices, or intrathecal devices.
  • the surface is a stent, it may be of any kind, but in specific cases the stent is a biliary stent, coronary, urethral/prostatic, urinary, vascular, CHD, esophageal, duodenal, colonic, or pancreatic stent.
  • the catheter When the surface is a catheter, it may be any kind of catheter, although in specific aspects the catheter is an indwelling catheter, such as a central venous catheter, a peripheral intravenous catheter, an arterial catheter, a Swan-Ganz catheter, a hemodialysis catheter, an urinary catheter, a peritoneal catheter, an umbilical catheter, a percutaneous nontunneled silicone catheter, a cuffed tunneled central venous catheter or a subcutaneous central venous port.
  • an indwelling catheter such as a central venous catheter, a peripheral intravenous catheter, an arterial catheter, a Swan-Ganz catheter, a hemodialysis catheter, an urinary catheter, a peritoneal catheter, an umbilical catheter, a percutaneous nontunneled silicone catheter, a cuffed tunneled central venous catheter or a subcutaneous central venous port.
  • a surface in a medical environment is contacted such as on drapes, a mattress, a pillow, a pillowcase, a sheet, laundry, wall, cabinet, drain, sink, toilet, bathtub, shower, countertop, waste receptacle, medical device, or medical equipment, for example.
  • the surface is an organic surface, such as skin, surgical suture, mucosal membrane surface, or epithelial surface.
  • the organic surface may be an oral cavity or other mucosal surface.
  • the surface is an inorganic surface, such as the surface of a pipe, a floor, a table-top, a counter-top, hospital equipment, a toy, an eating surface, high chair, medical equipment, medical device, phone, computer, kitchen sponge, faucet, light switch cover, doorknob, door, wall, razor, manicure or pedicure equipment, personal digital assistant, MP3 player, upholstery, bed linens, water fountain, or a wheel chair, for example.
  • the inorganic surface is plastic, glass, marble, ceramic, vinyl, stone, or metal.
  • the pipe may be of any kind, but in specific cases the pipe is an oil pipeline, gas pipeline, a water pipeline, an ice machine pipe, or a beverage-dispensing pipe, for example.
  • Contacting the surface may include contact of a hard surface or a soft surface or both.
  • the surface is in or on a gym, healthcare facility, camp, restroom, restaurant, school, daycare, cruise ship, household, mall, elevator, office building, kitchen, bedroom, hotel, motel, shower, airport, airplane, bus, car, train, boat, bus station, train station, marina, park, changing table, or stroller.
  • kits for disinfecting a surface to reduce microorganisms thereon comprising an antimicrobial composition of any the invention, wherein the biguanide and the glycol ether are contained in separate containers or a single container.
  • the kit comprises at least one alkylpolyglucoside, at least one chelator, at least one alchohol, deoxycholate, and/or glycerol.
  • the alcohol, the chelator, the deoxycholate, the glycerol and/or the alkylpolyglucoside are each contained in separate containers.
  • At least two of the glycol ether, the guanidinium compound, the chelator, deoxychoalte, glycerol, and the alkylpolyglucoside are contained in a suitable container. In some embodiments, at least three of the glycol ether, the biguanide, the chelator, deoxycholate, glycerol, and the alkylpolyglucoside are contained in a suitable container means.
  • the chelator is lyophilized or otherwise constituted as a dried powder, in certain aspects.
  • the kit may further comprise a second carrier solution for reconstituting the dried chelator.
  • the kit may comprise a lyophilized unit dose of a pharmacologically effective amount of the guanidium compound and the chelator to be mixed in an ethanol solution.
  • the surface is the surface of a medical device, a pipe, a floor, a table-top, a counter-top, an eating surface, a toy, a high chair, medical equipment, a wheel chair, a phone, a computer, a kitchen sponge, a faucet, light switch cover, a door knob, a door, razor, manicure or pedicure equipment, personal digital assistant, an MP3 player, upholstery, a water fountain, wall, razor, manicure or pedicure equipment, personal digital assistant, MP3 player, upholstery, bed linens, or water fountain.
  • the medical device may be a catheter.
  • the kit may further comprise a means for introducing the kit components into the medical device or the pipe.
  • a syringe comprising a unit dose of a pharmacologically effective amount of the solution of an antimicrobial composition of the invention.
  • a vial comprising a lyophilized unit dose of a pharmacologically effective amount of the solution of an antimicrobial composition of the invention.
  • an antimicrobial composition comprising at least one biguanide and one of the following: a) deoxycholate; or b) a combination of at least one chelator, at least one alcohol, and at least one alkylpolygluco side .
  • FIG. 1 compares particular exemplary combinations of CHX + Glucopon® or CHX + Dowanol® to other components or combinations, with exposures of one minute.
  • FIG. 2 compares certain exemplary triple combinations of CHX + Dowanol® + Glucopon® to other components or combinations, with exposures of 1 minute.
  • FIGS. 3A-3C compare the activity of combinations of 0.06% CHX + Dowanol® with and without 4% Glucopon® against various resistant gram- positive (VRE) (FIG. 3A) and gram-negative bacteria (e.g., Pseudomonas aeruginosa (FIG. 3B) and Acinetobacter baumanni (FIG. 3C).
  • VRE resistant gram- positive
  • FIGS. 3A-3C compare the activity of combinations of 0.06% CHX + Dowanol® with and without 4% Glucopon® against various resistant gram- positive (VRE) (FIG. 3A) and gram-negative bacteria (e.g., Pseudomonas aeruginosa (FIG. 3B) and Acinetobacter baumanni (FIG. 3C).
  • FIG. 4 shows efficacy of environmental solution containing 0.5% CHG, 3%CaEDTA, and 10% EtOH with and without 4% Glucopon®.
  • FIG. 5 shows efficacy of environmental solution containing 0.5% CHG, 3%CaEDTA, and 5% EtOH with and without 4% Glucopon®.
  • FIG. 6 shows activity of lock solutions against MRSA.
  • FIG. 7 shows activity of lock solutions against Pseudomonas aeruginosa.
  • FIG. 8 shows activity of lock solutions against Candida glabrata.
  • a or “an” may mean one or more.
  • the words “a” or “an” when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.
  • another may mean at least a second or more.
  • Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and/or methods of the invention. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.
  • antibacterial agent is defined as a compound having either a bactericidal or bacteriostatic effect upon bacteria contacted by the compound.
  • bactericidal is defined to mean having a destructive killing action upon bacteria.
  • bacteriostatic is defined to mean having an inhibiting action upon the growth of bacteria.
  • antifungal agent is defined as a compound having either a fungicidal or fungistatic effect upon fungi contacted by the compound.
  • fungicidal is defined to mean having a destructive killing action upon fungi.
  • fungistatic is defined to mean having an inhibiting action upon the growth of fungi.
  • an "antimicrobial agent” is defined herein as an agent that has antibiotic properties against bacteria, fungi, viruses and other pathogens and includes antibacterial agents, antifungal agents, antiviral agents and antiseptic agents. These components are present in effective amounts to reduce and/or prevent microbial growth.
  • antiviral agent is defined as a compound that can either kill viral agents or one that stops the replication of viruses upon contact by the compound.
  • biguanide which may be called diguanide or 2-carbamimidoylguanidine or guanylguanidine
  • biguanide refers to molecules based on the following exemplary structure:
  • bioenhancer is defined as an agent that does not achieve complete or near complete kill on its own but complements the antimicrobial activity of another such that the combination achieves near or complete kill.
  • near kill refers to a substantial reduction in microbial growth that either equals to or exceeds 99.9% kill.
  • a chelator denotes one or more chelators.
  • the term “chelator” is defined as a molecule comprising nonmetal atoms, two or more of which atoms are capable of linking or binding with a metal ion to form a heterocyclic ring including the metal ion.
  • the phrase "effective amount” or “therapeutically effective amount” is defined as a dosage sufficient to induce a microbicidal or microbistatic effect upon the microbes contacted by the composition on a surface.
  • compositions disclosed in the present invention are used to describe the process by which any of the compositions disclosed in the present invention, comes in direct juxtaposition with the surface of a medical device or any other surface from which microbial growth is to be reduced or eradicated.
  • Microorganisms that attach themselves to inert surfaces such as medical devices including, vascular catheters, endotracheal tubes, Foley catheters, biliary stents, nephrostomy tubes, prosthetic valves, ventriculostomy or epidural catheters, or fluid pipelines, such as oil pipelines or water pipelines, produce a layer made of exopolysaccharide called microbial biofilm. These organisms embed themselves in this layer. This biofilm layer ultimately becomes the protective environment that shields these organisms on the inert surface from the antimicrobial activity of various antibiotics or antiseptics.
  • medical devices including, vascular catheters, endotracheal tubes, Foley catheters, biliary stents, nephrostomy tubes, prosthetic valves, ventriculostomy or epidural catheters, or fluid pipelines, such as oil pipelines or water pipelines.
  • chelator and/or anticoagulant such as EDTA or heparin
  • the present invention regards a combination of antimicrobials that has at least two active components including (1) a guanidium compound, such as chlorhexidine, for example; (2) a glycol ether, such as dipropylene glycol n-butyl ether; and, optionally (3) a bioenhancer, for example, a Glucopon® surfactant or deoxycholate, and/or EDTA, and/or alcohol, and/or glycerol.
  • a guanidium compound such as chlorhexidine
  • a glycol ether such as dipropylene glycol n-butyl ether
  • a bioenhancer for example, a Glucopon® surfactant or deoxycholate, and/or EDTA, and/or alcohol, and/or glycerol.
  • This combination is highly safe, effective and, unlike the currently used disinfectants, fulfills one or more criteria that are useful for a universal ideal optimal disinfectant: broad-spectrum activity against various pathogens; no potential health risk to personnel or users (as is the case with chlorine bleach solutions, phenolic based solutions, and quarternary ammonium chlorides; no hazardous properties (such as being flammable, volatile, corrosive, or toxic, for example); stable at a wide range of pH; active in the presence of contaminants, including soil and water; active during a rapid unit of time (such as a minute, for example); minimal requirement for disposal with minimal biohazard concerns; and/or cost-effective.
  • the present invention utilizes low concentrations of very safe disinfectants, such as combinations including chlorhexidine, Glucopon®, Dowanol®, and/or deoxycholate, which demonstrate unexpected synergy with a high efficacy and an exceptional degree of safety to the end user and the environment.
  • very safe disinfectants such as combinations including chlorhexidine, Glucopon®, Dowanol®, and/or deoxycholate
  • An aspect of the present invention is based on the observation that solutions containing a glycol ether and a guanidinium compound, optionally with a chelator, an alkylpolyglucoside, an alcohol, and/or glycerol, exhibit surprising and unexpected increases in antimicrobial properties.
  • solutions containing combinations of two or three or more of an alcohol, a guanidinium compound, a chelator, deoxycholate and an alkylpolyglucoside may be used to achieve antimicrobial effects.
  • the antimicrobial solutions may be used with minimal or no toxicity to the user or recipient, such as a subject whose skin is cleaned prior to a surgical procedure.
  • Antimicrobial compositions described herein may be used for the rapid reduction or eradication of microorganisms embedded in a biofilm on a surface comprising contacting or exposing the surface to a flush solution of the invention.
  • the invention provides methods for reducing or eradicating microbes from the surfaces of medical devices, including indwelling medical devices, as well as other surfaces, pipelines and the like.
  • compositions and the methods of the present invention have an unexpected and surprising efficacy not provided by compositions that comprise only alcohol solutions, or at least certain compositions that comprise combinations of antimicrobials with chelators/anticoagulants.
  • intralumenal colonization is the major source for the migration of organisms leading to bloodstream infections in long-term silicone catheters (Raad et al., 1993)
  • recent guidelines by the CDC and Infectious Diseases Society of America have proposed the use of intralumenal antimicrobial lock solutions for the prevention and treatment of CRBSI (Mermel et al., 2001; Centers for Disease Control and Prevention, 2002).
  • Most long-term CVCs are typically flushed with heparin.
  • M-EDTA minocycline and EDTA
  • M-EDTA has been found to be efficacious in preventing CRBSI, this solution may not be applicable given some of the limitations of the real world of clinical practice.
  • the M-EDTA lock solution was required to be exposed to the surface of the indwelling medical device, such as the lumen of catheters, for at least 4 hours.
  • M-EDTA requires at least 4 hours of dwell time to eradicate organisms that colonize the lumen of the catheter (see U.S. Patent 5,362,754 and U.S. Patent 5,688,516).
  • Providing a four hour exposure time to reduce microbes using the M- EDTA solution is usually not possible in critically ill patients who require continuous infusion therapy, including parenteral nutrition.
  • One of the applications of the antimicrobial flush solutions of the invention is to reduce or eradicate microbes from the surfaces of medical devices, especially indwelling medical devices such as catheters, endotracheal tubes, nephrostomy tubea, biliary stents, orthopedic devices, prosthetic devices, and/or medical implants, for example.
  • indwelling medical devices such as catheters, endotracheal tubes, nephrostomy tubea, biliary stents, orthopedic devices, prosthetic devices, and/or medical implants, for example.
  • indwelling vascular catheters Irrespective of whether heparin is used, almost 90%- 100% of indwelling vascular catheters end up being colonized with organisms embedded in biofilm on the surface of these devices, particularly at the lumenal surface. Hence, the most serious and frequent complication of vascular catheters is infection, whereby as fluid is flushed through the lumen of the catheter, microorganisms migrate into the bloodstream and cause catheter-related bloodstream infections. Indwelling central venous catheters are associated with around 5%-8% frequency of catheter-related bloodstream infection, which in turn is associated with an attributable mortality of 25% in critically ill patients. Such an event is also associated with high morbidity and a cost per episode of an average of $30,000.
  • EDTA is a well-known chelator of iron and calcium, as well as an active anticoagulant used in blood collection tubes. EDTA has been shown to have equivalent anticoagulant activity to heparin. In addition, EDTA has antibiofilm activity and enhances the antimicrobial activity of other antimicrobial agents, such as minocycline. However, for a combination of an antmicrobial with a chelator (such as minocycline-EDTA) to eradicate organisms embedded in biofilm, contacting the surface for at least 4-hour with this combination is required. This is demonstrated in U.S. Patent 5,362,754 and in U.S. Patent 5,688,516.
  • indwelling medical devices such as catheters are flushed with an antimicrobial solution as described herein, resulting in broad- spectrum reduction or eradication of microbial organisms embedded in biofilm.
  • Angioplasty devices, heart valves and cardiac pacemakers also are included within the present invention, in certain embodiments.
  • Catheters such as urinary, venous, arterial, and peritoneal catheters may be treated with the flush solutions of the invention, for example.
  • tracheotomy devices, shunts, surgical sutures, and other medical devices or prosthesis can be treated, in particular aspects.
  • the medical devices that are amenable to coatings of the compositions of the invention generally have surfaces composed of thermoplastic or polymeric materials, such as polyethylene, Dacron, nylon, polyesters, polytetrafluoroethylene, polyurethane, latex, silicone elastomers and the like.
  • Devices with metallic surfaces are also amenable to coatings with the antibiotic combinations. Such devices are exemplified by bone and joint prosthesis. It is also contemplated that the solutions of the invention will be used to disinfect organic surfaces such as skin as well as mucosal surfaces.
  • An antimicrobial locking solution of the present invention may comprise at least at least one glycol ether, at least one alcohol, at least one guanidinium compound, at least one chelator, and/or at least one alkylpolyglucoside.
  • various antimicrobial substances as disclosed herein and that are well known to one of ordinary skill in the art may be combined with the locking solution in order to inhibit infection.
  • the antimicrobial locking solution of the present invention may be use for filling or flushing a medical device such as an indwelling device such as an implanted catheter. Other medical devices that are contemplated for use in the present invention are disclosed herein.
  • the flush solutions of the present invention are also useful in the eradication of the surfaces of other surfaces that microbes can grow on such as pipes, pipelines etc.
  • Fluid pipelines such as oil and water pipelines
  • lumenal biofilm that is produced by microorganisms that colonize the internal surface of these pipelines.
  • these pipelines are flushed with antimicrobial agents.
  • antimicrobial and antiseptic agents have little activity against organisms embedded in biofilm. Tons of antibiotics, such as gentamicin, are often used to flush the lumen of oil pipelines, to no avail.
  • the present invention provides new and effective compositions and methods for the eradication of organisms, as well as biofilm embedding the lumen of pipelines (oil, water), as well as other devices, such as ice machines.
  • These pipelines or machines can be flushed or rinsed with the compositions of the invention that comprise at least one antimicrobial compositions of the invention. Flushing the pipelines, machines or tubes with the compositions of the invention provide rapid reduction and/or eradication of the biofilm and the organisms in biofilm thereby preventing any obstruction or contamination of the water, oil or the ice machines in certain environmental settings.
  • compositions are contemplated to have one or more antimicrobial agents.
  • Antimicrobial agents are defined herein as antibacterial agents, antifungal agents, antiviral agents and/or antiseptic agents.
  • antimicrobial agent some exemplary classes and examples of antibacterial agents, antifungal agents, antiviral agents as well as antiseptic agents are described elsewhere herein. Of course one of skill in the art will appreciate that any combination as well as agents from the different types and classes of the antimicrobial agents can be combined to prepare the solutions of the invention.
  • Some non-limiting exemplary bacterial and fungal microbes that can be reduced or eradicated by the compositions and methods of the invention include Staphyloccous species such as Staphylococcus epidermidis, Staphylococcus aureus; Aspergllus species, such as Aspergillus flavus, Aspergillus terreus; Fusarium oxysporum, Candida species, such as Candida krusei, Candida parapsilosis, Candida tropicalis, Candida albicans and Candida glabrata.
  • viruses can also be reduced or eradicated.
  • Alkylpolyglucosides are a class of non-ionic surfactants that may be used in homes and/or personal care products, such as baby shampoos, facial cleaners, wipes, laundry detergents, or hard surface cleaners.
  • Various alkylpolyglucosides may be made from sugar and a vegetable oil such as coconut oil. Alkylpolyglucosides are typically very mild on human skin and exhibit low ecotoxicity.
  • one or more non-ionic surfactants may be included in an antimicrobial composition of the present invention.
  • an antimicrobial composition comprising chlorhexidine, a glycol ether, an alcohol (e.g., ethanol or isopropyl alcohol), and/or a chelator (e.g., CaEDTA) may also comprise an alkylpolyglucoside such as, for example, capryl glucoside, decyl glucoside, coco-glucoside, or lauryl glucoside.
  • alkylpolyglucosides are commercially available as Glucopon ® products from Cognis (Monheim, Germany).
  • 3%CaEDTA may be slowly dissolved in an alkylpolyglucoside and then an alcohol (e.g., ethanol) may be added to achieve a concentration range, e.g., below 10% total alcohol, and then chlorhexidine may be added to achieve a concentration, e.g., below about 1.5%.
  • an alcohol e.g., ethanol
  • chlorhexidine may be added to achieve a concentration, e.g., below about 1.5%.
  • alkylpolyglucoside refers to a compound having the following structure:
  • R is an C 2 -C 20 alkyl, more preferably a C 4 -C 14 alkyl.
  • R may be a C n alkyl, wherein n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • R is an unsubstituted alkyl; it is nonetheless considered that R may be a substituted alkyl in various embodiments.
  • alkyl when used without the "substituted” modifier refers to a non-aromatic monovalent group with a saturated carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon- carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • the groups, -CH 3 (Me), -CH 2 CH 3 (Et), -CH 2 CH 2 CH 3 (n-Pr), -CH(CH 3 ) 2 (iso-Pr), -CH(CH 2 ) 2 (cyclopropyl), -CH 2 CH 2 CH 2 CH 3 (n-Bu), -CH(CH 3 )CH 2 CH 3 (sec-butyl), -CH 2 CH(CH 3 ) 2 (iso-butyl), -C(CH 3 ) 3 (tert-butyl), -CH 2 C(CH 3 ) 3 (neo-pentyl), cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting examples of alkyl groups.
  • substituted alkyl refers to a non-aromatic monovalent group with a saturated carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom independently selected from the group consisting of N, O, F, CI, Br, I, Si, P, and S.
  • substituted alkyl groups are non-limiting examples of substituted alkyl groups:
  • alkylpolyglucosides include: capryl glucoside:
  • coco-glucoside octyl glucoside, such as
  • Non-limiting examples of surfactants that may be included in an antimicrobial composition, as described herein, are provided below in Table 1.
  • Technical data for the below surfactants is known in the art and available, e.g., from Chemidex (see Chemidex website).
  • chlorhexidine or a chlorhexidine derivative may be included in various antimicrobial compositions presented herein, it is anticipated that one or more basic reagents that exhibit an antimicrobial property may be substituted for, or used in combination with, chlorhexidine. It is anticipated that certain guanidium compounds, such as alexidine or hexamidine may be substituted for or used in combination with chlorhexidine.
  • the basic reagent can be an alkyl or aryl oxide, thiol, sulfide, phosphorous, aliphatic or aromatic amine, guanidinium compound or a halide such as F-, Br- and ⁇ .
  • phenoxide antiseptics such as clofoctol, chloroxylenol, triclosan
  • guanidium compounds such as chlorhexidine, alexidine, hexamidine
  • bipyridines such as octenidines
  • guanidium compounds include chlorhexidine, alexidine, and hexamidine.
  • the basic reagent is a bipyridine.
  • a bipyridine is octenidine.
  • the basic reagent is a phenoxide antiseptic.
  • a chelate is the type of coordination compound in which a central metal ion is attached by coordinate links to two or more nonmetal atoms in the same molecule. Heterocyclic rings are thus formed during chelation, with the metal atom as part of the ring.
  • the molecule comprising the nonmetal linking atoms is termed a chelator.
  • Chelators are used in various chemical applications, for example as titrating agents or as metal ion scavengers. Chelators can be used to remove ions from participation in biological reactions. For example, the well-known chelator ethylenediamine-N,N,N',N',-tetraacetic acid (EDTA) acts as an anticoagulant because it is capable of scavenging calcium ions from the blood.
  • EDTA ethylenediamine-N,N,N',N',-tetraacetic acid
  • chelators have significant growth inhibitory effect against several microbes. It is known that iron and other trace metals are essential in the life cycle of microorganisms such as fungi and bacteria. Without these trace metals, microbes are unable to grow and reproduce. Although iron is abundant in nature, its availability for microbial assimilation is limited owing to the insolubility of ferric ions at neutral or alkaline pH. As a consequence, many microbes have evolved their own specialized trace metal- scavenging molecules, called siderophores, which bind with trace metals and make them available for uptake by the microbes.
  • the chelators used in conjunction with the present invention provide an inhibitory effect upon microbial pathogens by competing with the siderophores for any available trace metal ions.
  • the chelators present in the pharmaceutical preparations of the present invention "steal" the metal ions essential for microbial growth, effectively causing the microbe to "starve to death.”
  • the additional antibiotic agents and the ethanol of the compositions of the present invention then come in and attack the weakened microbe, thereby destroying them or inhibiting their growth.
  • Table 2 below provides a representative list of chelators useful in conjunction with the present invention. However, the list provided in Table 2 is not meant to be exhaustive. Some useful chelators are those which bind trace metal ions with a binding constant ranging from 10 1 to 10 100 . More preferred chelators are those which bind trace metal ions with a binding constant ranging from 10 10 to 10 80 ; and most preferred chelators are those which bind trace metal ions with a binding constant ranging from 10 15 to 10 60 . Furthermore, preferred chelators are those which have been shown to have an inhibitory effect upon target microbial pathogens, for example the disodium salt of EDTA.
  • anticoagulants such as EGTA, EDTA, heparin, urokinase, streptokinase, low molecular weight heparin, enoxaparin, sodium coumarin, indanedione, anisindione, warfarin, protamine sulfate, anti-thrombin III, nitrilotriacetic acid, potassium sodium tartrate, potassium hydrogen D-tartrate, L-tartaric acid dipotassium salt, L-tartaric acid disodium salt, L-tartaric acid monosodium salt, tris(carboxymethyl)amine, warfarin, acetylsalicylic acid, ibuprofen, indomethacin, prostaglandins, sulfinpyrazone, streptokinase, urokinase, tissue plasminogen activator, coumarin,
  • the solutions of the instant invention are contemplated to comprise an alcohol, such as an antiseptic or disinfectant alcohol, in certain embodiments.
  • exemplary alcohols include ethanol, methanol, isopropanol, benzyl alcohol, chlorobutanol, phenylethyl alcohol, 2-bromo-2-nitropropan-1,3-diol, and the like.
  • the present invention contemplates any effective concentration of alcohol, but will typically employ a final alcohol concentration in the range of about 5%-80% (v/v), more preferably in the range of about 10% to about 50%, more preferably in the range of 15% to 40%, more preferably in the range of about 20% to about 30%, with the most preferable being about 25%.
  • the more preferred concentration of alcohol will include about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or about 80% (v/v) of the alcohol in the preparation of the instant antimicrobial solutions.
  • Alcohols such as ethanol are long known to have disinfectant properties.
  • EP1245247 and U.S. Patent 6,350,251 it is reported that the combination of ethanol with EDTA provides a biocidal lock for indwelling medical devices.
  • a combination of ethanol with EDTA is less effective in killing microbes than ethanol alone (Sherertz et ah, 2002).
  • the art is in a flux about the exact role of the combination of ethanol with EDTA.
  • the present inventor has shown that ethanol alone, while requiring only a relatively short duration of contact, is only partially effective in killing or controlling microbes on the surface of an indwelling medical device or other surface.
  • a combination of an antimicrobial agent and a chelator such as EDTA may be effective, yet it requires a somewhat longer duration of contact (e.g., sometimes on the order of 4 hours).
  • certain embodiments provide unexpectedly effective anti-microbial properties in a very short duration and in addition to eradicating microbes rapidly from a surface they also preventing re-growth of the microbial pathogen on the surface.
  • An additional advantage for the combination is that it is effective at eradicating a broader range of microbial organisms (bacteria and fungi), even at the shorter durations of contact with the treated surface.
  • any additional pharmacologically active ingredients or sterilization agents may be comprised in the solutions of the present invention or may be used separately for flushing or treating the devices of the present invention to further reduce or eliminate pathogenic microbes and viruses.
  • Typical pharmacologically active ingredients include antifibrin agents, anti-thrombotic agents, and anti-inflammatory agents.
  • Anti-inflammatory agents include steroids, and nonsteroidal anti-inflammatory agents, and salicylates.
  • Anti-thrombotic drugs including acetylsalicylic acid, dipyridamole, heparin, ibuprofen, indomethacin, prostaglandins, sulfinpyrazone, warfarin, thrombolytic enzymes such as streptokinase, urokinase, or plasminogen activator.
  • Complexing agents such as ammonium- 1 -pyrrolidine dithiocarbanate may also be used.
  • the above examples are not meant to be limiting.
  • kits [0153] Described herein are various packaging techniques that may be employed in providing the flush solutions of the invention as part of a commercially available kit.
  • the kit will optionally include an instruction sheet insert to identify how the kit is to be used.
  • the kit may comprise of one or two or three or more compartments.
  • the components of the kit may be provided in separate compartments or in the same compartment.
  • the components of the kit may be provided separately or mixed.
  • the mixed components may contain two or more components such as a guanidium compound, a glycol ether, and/or no other component, a chelator, alcohol, deoxycholate, or one or more additional components.
  • One of the packaging options below maintain the ingredients, for example, the antibiotic, such as minocycline, and the chelating agent/anticoagulant, such as EDTA, in an uncombined form. These components are to be combined shortly before use. These packaging options are contemplated to be part of a 2-compartment or three- compartment container system to provide a total volume of about 3 ml of the ready to use preparation. Any compartmentalized container system may be used to package the compositions of the present invention. An exemplary container system is available from Becton Dickinson.
  • kits comprising a container means comprising a volume of diluent, comprising an alcohol optionally diluted if required in a solution such as saline or sterile water, a second (or more) container means comprising one or more antimicrobial or biocide, a third (or more) container means comprising one or more chelating/anticoagulant agent.
  • a container means comprising a volume of diluent, comprising an alcohol optionally diluted if required in a solution such as saline or sterile water
  • a second (or more) container means comprising one or more antimicrobial or biocide
  • a third (or more) container means comprising one or more chelating/anticoagulant agent.
  • the dry components may optionally be mixed in one compartment.
  • the addition of the diluent would then be performed immediately prior to use.
  • the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which the antimicrobial/chelator/anticoagulant/alcohol may be placed, and preferably, suitably aliquoted. Where one or more other antimicrobial components are provided, the kit will also generally contain a second, third or other additional container into which this component may be placed.
  • the kits of the present invention will also typically include a means for containing the one or more components and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow- molded plastic, or glass containers into which the desired vials are retained.
  • the aim of these sets of experiments is to compare the activity of these various solutions on a 10-set slid carriers of MSRA using standard EPA quantitate carrier test in 25-50% calf serum. According to a scale derived from the EPA standards, we have established that for a disinfectant to be highly effective, it should completely kill the MRS A on 9 out of 10 of the carriers and the 1 out of 10 positive carriers should involve at least 99% reduction in CFU.
  • Experiment Set 1 Comparing combinations of CHG + Glucopon® or CHG + Dowanol® to other components or combinations (See Table 3 and FIG. 1).
  • Glucopon® or Dowanol® act as bioenhancers of chlorhexidine leading to complete and rapid eradication of MRSA.
  • These surfactants/detergents do not eradicate resistant bacteria on their own (either alone or in combination) but rather enhance the activity of low concentration chlorhexidine. The same is true for deoxycholate.
  • the present invention regards the combination of guanidium compounds with surfactants or detergents such as Glucapon®, Dowanol®, or deoxycholate.
  • SOP method quantitative germicidal spray
  • 10 slide carriers were inoculated with 10 5 (in 50% calf serum) of MRSA, VRE, multidrug-resistant (MDR) Acinetobacter (ACN), MDR Pseudomonas aeruginosa (PSA) and fluconazole-resistant Candida glabrata (CG), and then they were exposed briefly (1 minute) to the antiseptics.
  • MDR multidrug-resistant
  • PSA MDR Pseudomonas aeruginosa
  • CG fluconazole-resistant Candida glabrata
  • CHG chlorhexidine
  • Glucopon® 5% Dowanol® alone or in combination.
  • EXPERIMENT SET 1 Comparing combinations of CHX + Glucopon®or CHX + Dowanol® to other components or combinations, with experimental exposure lasting 1 minute. As shown in FIG. 1, only the combinations consisting of CHX + Dowanol® passed the test of being highly effective against MRSA (as a form of a resistant bacteria) with 10 out of 10 carriers being negative for CHX + Dowanol® showing rapid >99.9% reduction in colonies after only 1 minute of exposure.
  • the surfactant Glucopon® acts as a booster of chlorhexidine plus low concentration of Dowanol® leading to complete and rapid eradication of MRSA. These surfactants/detergents do not eradicate resistant bacteria on their own but rather enhance the activity of low concentration chlorhexidine in combination with low concentrations of Dowanol®. The same is true for deoxycholate, in particular aspects of the invention.
  • EXPERIMENT SET 2 Comparing the triple combinations of CHX + Dowanol® + Glucopon® to other components or combinations: (See FIG. 2), with experimental exposure lasting one minute. As shown in FIG. 2, only the combinations consisting of low concentration CHX + low concentration Dowanol®+ Glucopon® passed the test of being highly effective against MRSA as a form of a resistant bacteria with 10 out of 10 carriers being negative for showing rapid >99.9% reduction in colonies after only 1 -minute of exposure.
  • EXPERIMENT SET 3 Comparing the activity of combinations of 0.06% CHX + Dowanol® with and without 4% Glucopon® against various resistant gram-positive (VRE) and gram-negative bacteria (e.g., Pseudomonas aeruginosa and Acinetobacter baumanni.
  • VRE resistant gram-positive
  • gram-negative bacteria e.g., Pseudomonas aeruginosa and Acinetobacter baumanni.
  • Dowanol® acts as a bioenhancer of chlorhexidine leading to complete and rapid eradication of MRSA. This bioenhancer does not eradicate resistant bacteria on its own but rather enhances the activity of low concentration chlorhexidine.
  • the surfactant Glucopon® acts as booster of chlorhexidine plus low concentration of Dowanol® leading to complete and rapid eradication of MRSA.
  • the present Example concerns determination of the optimal concentration of EtOH to be added to the antiseptic environmental solution and to determine whether the addition of 4% Glucopon® enhances this efficacy.
  • Efficacy of various combinations of 0.5% chlorhexidine digluconate (CHG) + 3%CaEDTA + 5 or 10% EtOH with our without 4% Glucopon® were tested using a modification of the standard operating procedure (SOP) for quantitative evaluation of germicidal spray.
  • SOP standard operating procedure
  • Ten microscope slides were inoculated independently with 20uL of 4 multidrug resistant (MDR) organisms at a concentration of lxlO 5 CFU/mL in 50% calf serum.
  • MDR multidrug resistant
  • Organisms tested include methicillin resistant Staphylococcus aureus (MRSA 4798), Vancomycin resistant entercocci (EN 3868), MDR-Pseudomonas aeruginosa (PS 4689), and Candida albicans. Slides were placed in covered sterile Petri dishes and dried at 37°C for 1 hour to ensure complete drying. Samples were then briefly exposed (1 minute) to antiseptic environmental solutions. After exposure slides were immediately immersed in 20mL of D/E Neutralizing Broth, capped, and shaken by hand in order to ensure thorough covering by the neutralizing broth to stop all antiseptic activity. Resulting broth was then serially diluted and spread on agar plates, Trypticase Soy Agar with 5%.
  • Staphlyococcus aureus (MRSA 4798), Vancomycin-resistant entercocci (VRE 3868), MDR - Pseudomonas aeruginosa (PS 4689), and Candida albicans.
  • Exemplary solutions tested included 0.5%CHG + 3%CaEDTA + 10%EtOH; 0.5%CHG + 3%CaEDTA + 10%EtOH + 4%Glucopon; 0.5%CHG + 3%CaEDTA + 5%EtOH; and 0.5%CHG + 3%CaEDTA + 5%EtOH + 4% Glucopon®.
  • FIG. 4 shows efficacy of environmental solution containing 0.5% CHG, 3%CaEDTA, and 10% EtOH with and without 4% Glucopon®.
  • FIG. 5 shows efficacy of environmental solution containing 0.5% CHG, 3%CaEDTA, and 5% EtOH with and without 4% Glucopon®.
  • this present Example demonstrates that precipitation occurred upon mixing both the 5% and 10% EtOH solutions without Glucopon®. With the addition of 4% Glucopon® no precipitation occurred. The addition of 4% Glucopon® enhances the environmental solution at both 5% and 10% concentrations of EtOH, for example, to completely eradicate all organisms.
  • the aim of experiment set 4 is to test the activity of 5% Dowanol® + Chlorhexidine 0.06% (CHX) or 50% Glycerol + CHX (0.06% or 0.12%) against various resistant bacteria and fungi.
  • Biofilm was grown on sterile silicone discs following a modified Kuhn's method. Briefly, silicone discs were placed into a 24 well tissue culture plate and incubated overnight at 37°C. The plasma was then removed and replaced with ImL of 5.5x105 CFU/mL inoculum of various organisms. The plates were then incubated for an additional 24hrs at 37 °C. Inoculum was then removed and discs were washed shaking for 30 minutes in 0.9% sterile saline. After washing the discs were placed in ImL of various antimicrobial solutions and incubated at 37°C for 2 hrs. The discs were then removed and placed in 5mL of 0.9% sterile saline and sonicated to disrupt any remaining biofilm.
  • the resulting solution was then quantitatively cultured by making serial dilutions in 0.9% sterile saline and plating on agar plates, TSA+5% sheep blood for all bacterial organisms and Sabouraud Dextrose Agar for yeasts. A total of 3-9 discs were used for both organisms and respective labs solutions (see Tables 4-6).
  • FIG. 6 shows activity of lock solutions against MRSA.
  • FIG. 8 demonstrates activity of lock solutions against Candida glabrata.
  • compositions and/or methods and/or apparati disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and/or apparati and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. [0224] References

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Abstract

La présente invention concerne des solutions antimicrobiennes qui, dans certains cas, comprennent un biguanide et un glycol éther et, dans certains cas, comprennent également éventuellement des combinaisons d'au moins un alcool, d'au moins un chélateur, de glycérol, de désoxycholate et/ou d'au moins un alkylpolyglucoside. Dans certains aspects, l'invention comprend un biguanide et un désoxycholate ou une combinaison d'un chélateur, d'éthanol et d'un alkylpolyglucoside. L'invention concerne également des procédés pour tuer et/ou réduire rapidement des bactéries, des champignons ou des virus sur des surfaces, par exemple, notamment, des surfaces de dispositifs médicaux à demeure et des surfaces organiques comme la peau et des sutures, et des surfaces inorganiques comme un équipement médical, des conduits, etc.
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